Growth and differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1(MIC-1), placental transforming growth factor-β, prostate-derived factor, and placental bone morphogenetic protein, is a divergent member of the transforming growth factor beta (TGF-β) superfamily (1 - 3). GDF-15 is initially synthesized as a 40 kDa inactive precursor protein. It is then proteolytically cleaved to release the active C-terminal fragment, which is assembled into a disulfide-linked homodimer of 28 kDa to become biologically active GDF-15 (1, 4). In humans, GDF-15 is predominantly expressed in the placenta, with low levels in the kidney, pancreas, and prostate. However, its expression can be rapidly induced by cytokines such as interleukin-1 and TGF-β (1 - 3).

GDF-15 has diverse biological functions. Early studies have shown that low serum GDF-15 levels correlate with miscarriages, indicating that it might be able to suppress inflammation in early pregnancy (5, 6). GDF-15 also plays an important role in tumorigenesis and metastasis. It has been observed that in many types of cancers, such as colorectal, breast, and prostate, the expression of GDF-15 is dramatically increased (7 - 9). Additionally, in cancer patients, serum levels of GDF-15 are elevated, which are of value in disease diagnosis and stratification (10 -12). GDF-15 is strongly induced by the tumor suppressor gene p53 and other anti-tumorigenic agents, such as the non-steroidal anti-inflammatory drugs and peroxisome proliferators-activated receptor γ. These findings suggest that GDF-15 may be a downstream target of those signaling pathways that regulate cell cycle arrest and apoptosis (13 - 15). Through the modulation of neuronal pathways important in the regulation of appetite and energy homeostasis, GDF-15 mediates cancer-induced anorexia and weight loss (16).